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Human and mouse Abelson interacting proteins (Abi) are SH3-domain containing proteins that bind to the proline-rich motifs of the Abelson protein tyrosine kinase. We report a new member of this gene family, a Drosophila Abi (dAbi) that is a substrate for Abl kinase and that co-immunoprecipitates with Abl if the Abi SH3 domain is intact. We have identified a new function for both dAbi and human Abi-2 (hAbi-2). Both proteins activate the kinase activity of Abl as assayed by phosphorylation of the Drosophila Enabled (Ena) protein. Removal of the dAbi SH3 domain eliminates dAbi's activation of Abl kinase activity. dAbi is an unstable protein in cells and is present at low steady state levels but its protein level is increased coincident with phosphorylation by Abl kinase. Expression of the antisense strand of dAbi reduces dAbi protein levels and abolishes activation of Abl kinase activity. Modulation of Abi protein levels may be an important mechanism for regulating the level of Abl kinase activity in the cell.

Many Drosophila genes have now been identified with substantial sequence similarity to vertebrate protooncogenes and growth factors. Some of these have been isolated directly by cross-hybridization with vertebrate probes and some have been recognized in the sequences of genes cloned because of their intiguing mutant phenotypes. An example of a gene isolated for its interesting development functions but with homology to a vertebrate growth factor is the Drosophila decapentaplegic gene (dpp). An example of a Drosophila gene isolated by virtue of its sequence conservation is the vgr/60A gene. Both dpp and vgr/60A are members of the transforming growth factor-β family and are most similar to the human bone morphogenetic proteins. The regulation of the dpp gene by several different groups of pattern formation genes including the dorsal/ventral group, the terminal group, the segment polarity genes, and the homeotic genes indicates that many events in embryogenesis require the cell to cell communication mediated by the secreted dpp protein. The temporal and spatial pattern of vgr/60A expression differs from that of dpp indicating that it may be regulated by different pattern information genes. The experimental advantages of the Drosophila system should permit a better understanding of the importance of growth factor homologs in specific developmental events, aid in establishing the functional interactions between these regulatory molecules, and identify new genes that are important for the biological functions of growth factors. It is likely that some of the newly identified genes will have vertebrate homologs and the analysis of these may be helpful in studies on vertebrate development and tumor biology. © 1992 Wiley-Liss, Inc.

We targeted expression of human/fly chimeric Bcr-Abl proteins to the developing central nervous system (CNS) and eye imaginal disc of Drosophila melanogaster. Neural expression of human/fly chimeric P210 Bcr-Abl or P185 Bcr-Abl rescued abl mutant flies from pupal lethality, indicating that P210 and P185 Bcr-Abl can substitute functionally for Drosophila Abl during axonogenesis. However, increased levels of neurally expressed P210 or P185 Bcr-Abl but not Drosophila Abl produced CNS defects and lethality. Expression of P210 or P185 in the eye imaginal disc produced a dominant rough eye phenotype that was dependent on dosage of the transgene. Drosophila Enabled, previously identified as a suppressor of the abl mutant phenotype and substrate for Drosophila Abl kinase, had markedly increased phosphotyrosine levels in Bcr-Abl expressing Drosophila, indicating that it is a substrate for Bcr-Abl as well. Drosophila, therefore, is a suitable model system to identify Bcr-Abl interactions important for signal transduction and oncogenesis.

SIGNALLING proteins in the BMP-decapentaplegic (dpp), WNT-wingless (wg) and Shh-hedgehog (hh) families have been implicated in limb and appendage development in both invertebrates and vertebrates1–3. In Drosophila, dpp protein (Dpp) induces distal outgrowth and patterning of legs and wings, but the molecular responses to Dpp are not well characterized4–9. Analysis of clones mutant for the Dpp receptors encoded by punt or thickveins (tkv) reveals that repression of wg expression is one critical function of Dpp signalling in leg and wing discs. Distal clones that lie on the anterior edge of the anterior–posterior compartment boundary ectopically express wg and cause pattern abnormalities, suggesting that Dpp represses Hh activation of wg in the distal primordia of the leg and wing. By repressing wg expression in the leg, Dpp signalling limits the region that responds to high levels of Wg and Dpp to the site of distal outgrowth. Such negative regulatory feedback loops between signalling molecules are likely to be critical for limb patterning in other species.

Genetic studies on Drosophila Abl and, more recently, on mouse c-Abl and c-Src indicate that the functions of these non-receptor tyrosine kinases may duplicate activities of other molecules within signal transduction pathways. In Drosophila, second-site mutations have been recovered that disrupt the redundant functions so that the Abl tyrosine kinase is essential to the formation of axonal connections in the embryonic central nervous system and for attachment of embryonic muscles to the body wall. Molecular isolation and analysis of the genes identified by these second-site mutations should define the molecular basis for the genetic redundancy.

The regulation of cell proliferation and differentiation is an essential aspect of organismal development. An important goal of investigations over the next few years will be to define the regulatory pathways of cellular proliferation and differentiation by discovering how the molecules we know about, and others that remain to be discovered, interact with one another to instruct a cell to divide or to differentiate. Growth factors, growth receptors, and the protooncogenes represent some of the components on these regulatory circuits; the challenge is to complete the “wiring-diagrams” by finding the molecular connections between the components. Molecular genetic and biochemical approaches are being applied to this problem in vertebrate cell culture and animal systems. The opportunity to use classical genetic strategies to address this problem led several groups to examine simpler organisms for the presence of proteins homologous to growth factors, growth factor receptors, or protooncogenes. It is now clear that many of these proteins have been well conserved during evolution and are found in three organisms eminently suited to genetic manipulation—yeast, Caenorhabditis elegans, and Drosophila melanogaster.